Preterm labor is an important public health problem that presents significant risks for both mother and child. Preterm labor occurs in an estimated ten percent of all pregnancies worldwide, which amounts to nearly 13 million affected births each year. Currently, infection is the only rigorously confirmed cause of preterm labor. Placental infections across gestational ages can result in spontaneous abortion, neonatal infection, and maternal and fetal morbidity and mortality. Remarkably, our understanding of how pathogens infect the placenta and lead to pregnancy complications remains extremely limited, largely due to the inherent intractability of this tissue. Thus, the long-term goal of this project is to use mdel systems to investigate host-pathogen interactions that occur during placental infection. Strikingly, the vast majority of known placental pathogens have intracellular lifestyles, suggesting that their placental pathogenesis may be similar. One such pathogen is Listeria monocytogenes, a ubiquitous and well studied bacterium that causes foodborne disease; infection with L. monocytogenes is known to induce preterm labor. We have chosen to use L. monocytogenes to explore placental pathogenesis. Recent studies from our lab have hinted at the innate immune mechanisms intrinsic to the placenta, including the histological barriers to pathogen invasion. Small subpopulations of placental cells called extravillous trophoblasts (EVTs) are susceptible to infection with L. monocytogenes. Importantly, these cells also limit L. monocytogenes growth and spread by degrading intracellular bacteria. However, under certain ill-defined conditions, L. monocytogenes can escape degradation in EVTs and spread throughout the placenta. We propose to first elucidate the mechanism by which EVTs restrict L. monocytogenes growth, as well as investigate whether this is a general innate immune pathway used to eliminate pathogens (Aim 1). In addition, we propose to clarify the conditions that allow L. monocytogenes escape by identifying and characterizing the function of novel bacterial virulence factors (Aim 2). These studies will contribute significantly to our understanding of host pathogen interactions in the placenta and will prove valuable in developing novel therapies to prevent or treat placental infections, leading to improved maternal and fetal health. PUBLIC HEALTH RELEVANCE: A significant portion of negative pregnancy outcomes are attributable to infection of the placenta by human pathogens. This application seeks to further our understanding of this process at the cellular level. Our results will inform the development of appropriate therapies, potentially reducing the incidence of preterm labor due to infection and improving overall public health.